Rare and Common Regulatory Variation in Population-Scale Sequenced Human Genomes

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Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs) when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs) discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function.

Vyšlo v časopise: Rare and Common Regulatory Variation in Population-Scale Sequenced Human Genomes. PLoS Genet 7(7): e32767. doi:10.1371/journal.pgen.1002144
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002144

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1. WheelerDASrinivasanMEgholmMShenYChenL 2008 The complete genome of an individual by massively parallel DNA sequencing. Nature 452 872 876

2. LevySSuttonGNgPCFeukLHalpernAL 2007 The diploid genome sequence of an individual human. PLoS Biol 5 e254 doi:10.1371/journal.pbio.0050254

3. BentleyDRBalasubramanianSSwerdlowHPSmithGPMiltonJ 2008 Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456 53 59

4. WangJWangWLiRLiYTianG 2008 The diploid genome sequence of an Asian individual. Nature 456 60 65

5. SchusterSCMillerWRatanATomshoLPGiardineB 2010 Complete Khoisan and Bantu genomes from southern Africa. Nature 463 943 947

6. RoachJCGlusmanGSmitAFHuffCDHubleyR 2010 Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328 636 639

7. NgSBTurnerEHRobertsonPDFlygareSDBighamAW 2009 Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461 272 276

8. DermitzakisET 2008 From gene expression to disease risk. Nat Genet 40 492 493

9. CheungVGSpielmanRS 2009 Genetics of human gene expression: mapping DNA variants that influence gene expression. Nat Rev Genet 10 595 604

10. DimasASDeutschSStrangerBEMontgomerySBBorelC 2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250

11. MontgomerySBDermitzakisET 2011 From expression QTLs to personalized transcriptomics. Nat Rev Genet

12. SpeliotesEKWillerCJBerndtSIMondaKLThorleifssonG 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet

13. DuboisPCTrynkaGFrankeLHuntKARomanosJ 2010 Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 295 302

14. AnttilaVStefanssonHKallelaMTodtUTerwindtGM 2010 Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 42 869 873

15. MontgomerySBSammethMGutierrez-ArcelusMLachRPIngleC 2010 Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464 773 777

16. StrangerBEMontgomerySBDimasAS… 2010 Patterns of cis regulatory variation in diverse human populations. in preparation

17. PastinenT 2010 Genome-wide allele-specific analysis: insights into regulatory variation. Nat Rev Genet 11 533 538

18. VeyrierasJBKudaravalliSKimSYDermitzakisETGiladY 2008 High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4 e1000214 doi:10.1371/journal.pgen.1000214

19. StrangerBENicaACForrestMSDimasABirdCP 2007 Population genomics of human gene expression. Nat Genet 39 1217 1224

20. DixonALLiangLMoffattMFChenWHeathS 2007 A genome-wide association study of global gene expression. Nat Genet 39 1202 1207

21. PickrellJKMarioniJCPaiAADegnerJFEngelhardtBE 2010 Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464 768 772

22. AndersenMCEngstromPGLithwickSArenillasDErikssonP 2008 In silico detection of sequence variations modifying transcriptional regulation. PLoS Comput Biol 4 e5 doi:10.1371/journal.pcbi.0040005

23. BirneyEStamatoyannopoulosJADuttaAGuigoRGingerasTR 2007 Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447 799 816

24. MontgomerySBGriffithOLSchuetzJMBrooks-WilsonAJonesSJ 2007 A survey of genomic properties for the detection of regulatory polymorphisms. PLoS Comput Biol 3 e106 doi:10.1371/journal.pcbi.0030106

25. DimasASStrangerBEBeazleyCFinnRDIngleCE 2008 Modifier effects between regulatory and protein-coding variation. PLoS Genet 4 e1000244 doi:10.1371/journal.pgen.1000244

26. NgSBBuckinghamKJLeeCBighamAWTaborHK 2010 Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42 30 35

27. ChoiMSchollUIJiWLiuTTikhonovaIR 2009 Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A 106 19096 19101

28. BilguvarKOzturkAKLouviAKwanKYChoiM 2010 Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467 207 210

29. DurbinRMAbecasisGRAltshulerDLAutonABrooksLD 2010 A map of human genome variation from population-scale sequencing. Nature 467 1061 1073

30. NielsenR 2010 Genomics: In search of rare human variants. Nature 467 1050 1051

31. HarrowJDenoeudFFrankishAReymondAChenCK 2006 GENCODE: producing a reference annotation for ENCODE. Genome Biol 7 Suppl 1 S4 1 9

32. FlicekPAmodeMRBarrellDBealKBrentS 2010 Ensembl 2011. Nucleic Acids Res

33. StoreyJDTibshiraniR 2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445

34. PollardKSHubiszMJRosenbloomKRSiepelA 2010 Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20 110 121

35. NicaACMontgomerySBDimasASStrangerBEBeazleyC 2010 Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 6 e1000895 doi:10.1371/journal.pgen.1000895